Inoculated mammary carcinoma-associated fibroblasts: contribution to hormone independent tumor growth

<p>Abstract</p> <p>Background</p> <p>Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF) in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD) tumors grow only in the presence of progestins, whereas hormone independent (HI) variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI) express high levels of FGF-2 and that FGF-2 induced HD tumor growth <it>in vivo</it>. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI) HD cells can induce HD tumor growth.</p> <p>Methods</p> <p>Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation.</p> <p>Results</p> <p>We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p < 0.001). Moreover, inoculated CAF-HI did not persist within the tumors. Immunofluorescence studies showed that inoculated CAF-HI disappeared after 13 days. We studied the mechanisms by which CAF-HI increased HI tumor growth, and found a significant increase in angiogenesis (p < 0.05) in the co-injected mice at early time points.</p> <p>Conclusions</p> <p>Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.</p

Dissection of ancestral genetic contributions to Creole goat populations

Goats have played a key role as source of nourishment for humans in their expansion all over the world in long land and sea trips. This has guaranteed a place for this species in the important and rapid episode of livestock expansion triggered by Columbus’ arrival in the Americas in the late 1400s. The aims of this study are to provide a comprehensive perspective on genetic diversity in American goat populations and to assess their origins and evolutionary trajectories. This was achieved by combining data from autosomal neutral genetic markers obtained in more than two thousand samples that encompass a wide range of Iberian, African and Creole goat breeds. In general, even though Creole populations differ clearly from each other, they lack a strong geographical pattern of differentiation, such that populations of different admixed ancestry share relatively close locations throughout the large geographical range included in this study. Important Iberian signatures were detected in most Creole populations studied, and many of them, particularly the Cuban Creole, also revealed an important contribution of African breeds. On the other hand, the Brazilian breeds showed a particular genetic structure and were clearly separated from the other Creole populations, with some influence from Cape Verde goats. These results provide a comprehensive characterisation of the present structure of goat genetic diversity, and a dissection of the Iberian and African influences that gave origin to different Creole caprine breeds, disentangling an important part of their evolutionary history. Creole breeds constitute an important reservoir of genetic diversity that justifies the development of appropriate management systems aimed at improving performance without loss of genomic diversity

MINERvA neutrino detector response measured with test beam data

The MINERvA collaboration operated a scaled-down replica of the solid scintillator tracking and sampling calorimeter regions of the MINERvA detector in a hadron test beam at the Fermilab Test Beam Facility. This article reports measurements with samples of protons, pions, and electrons from 0.35 to 2.0 GeV/c momentum. The calorimetric response to protons, pions, and electrons are obtained from these data. A measurement of the parameter in Birks' law and an estimate of the tracking efficiency are extracted from the proton sample. Overall the data are well described by a Geant4-based Monte Carlo simulation of the detector and particle interactions with agreements better than 4%, though some features of the data are not precisely modeled. These measurements are used to tune the MINERvA detector simulation and evaluate systematic uncertainties in support of the MINERvA neutrino cross section measurement program.Comment: as accepted by NIM

Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected children

Objective: To evaluate the effect of combined antiretroviral therapy on serum immunoglobulin (Ig) levels in HIV-1 perinatally infected children. Methods: Data from 1250 children recorded by the Italian Register for HIV Infection in Children from 1985 to 2002 were analysed. Since Ig levels physiologically vary with age, differences at different age periods were evaluated as differences in z-scores calculated using means and standard deviations of normal population for each age period. Combined antiretroviral therapy has become widespread in Italy since 1996, thus differences in Ig z-scores between the periods 1985-1995 and 1996-2002 were analysed. Data according to type of therapeutic regimen were also analysed. Results: Between the two periods 1985-1995 and 1996-2002, significant (P < 0.0001) decreases in IgG (6.29 ± 4.72 versus 4.44 ± 4.33), IgM (9.25 ± 13.32 versus 5.61 ± 7.93), and IgA (10.25 ± 15.68 versus 6.48 ± 11.56) z-scores, together with a parallel significant (P < 0.0001) increase in CD4 T-lymphocyte percentages, were found. These decreases were confirmed regardless of whether the children were receiving intravenous Ig or not. Ig z-scores were significantly higher in children receiving mono-therapy than in those receiving double-combined therapy (IgC, P < 0.0001; IgM, P = 0.003; IgA, P = 0.031) and in the latter children than in those receiving three or more drugs (P < 0.0001 for all z-scores). Ig z-scores correlated inversely with CD4 T-lymphocyte percentages and, directly, with viral loads. Conclusions: Our data show that in HIV-1 infected children combined antiretroviral therapy leads to reduction of hyperimmunoglobulinemia which parallels restoration of CD4 T-lymphocyte percentage and viral load decrease, which it turn probably reflects improved B-lymphocyte functions. © 2004 Lippincott Williams & Wilkins

Seagrass and submerged aquatic vegetation (VAS) habitats off the Coast of Brazil: state of knowledge, conservation and main threats

Seagrass meadows are among the most threatened ecosystems on earth, raising concerns about the equilibrium of coastal ecosystems and the sustainability of local fisheries. The present review evaluated the current status of the research on seagrasses and submerged aquatic vegetation (SAV) habitats off the coast of Brazil in terms of plant responses to environmental conditions, changes in distribution and abundance, and the possible role of climate change and variability. Despite an increase in the number of studies, the communication of the results is still relatively limited and is mainly addressed to a national or regional public; thus, South American seagrasses are rarely included or cited in global reviews and models. The scarcity of large-scale and long-term studies allowing the detection of changes in the structure, abundance and composition of seagrass habitats and associated species still hinders the investigation of such communities with respect to the potential effects of climate change. Seagrass meadows and SAV occur all along the Brazilian coast, with species distribution and abundance being strongly influenced by regional oceanography, coastal water masses, river runoff and coastal geomorphology. Based on these geomorphological, hydrological and ecological features, we characterised the distribution of seagrass habitats and abundances within the major coastal compartments. The current conservation status of Brazilian seagrasses and SAV is critical. The unsustainable exploitation and occupation of coastal areas and the multifold anthropogenic footprints left during the last 100 years led to the loss and degradation of shoreline habitats potentially suitable for seagrass occupation. Knowledge of the prevailing patterns and processes governing seagrass structure and functioning along the Brazilian coast is necessary for the global discussion on climate change. Our review is a first and much-needed step toward a more integrated and inclusive approach to understanding the diversity of coastal plant formations along the Southwestern Atlantic coast as well as a regional alert the projected or predicted effects of global changes on the goods and services provided by regional seagrasses and SAV

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

Comparing inequalities in the labour market from a segmentation perspective

Production of INCASI Project H2020-MSCA-RISE-2015 GA 691004The purpose of this chapter is to carry out a comparative analysis of labour markets in Europe and Latin America from the perspective of segmentation in order to explain the processes of social inequality that arise in the workplace, in light of recent trends in global socio-economic changes. The chapter proposes two main objectives. The first is to perform a comparative descriptive analysis of the main features of labour markets among 60 European and Latin American countries. The second objective is to propose a model of comparative analysis of labour inequality from the theoretical perspective of the segmentation of the labour market and structural heterogeneity. We will focus our analysis by selecting two countries, Spain and Argentina, which both underwent a late development of capitalism. The following general hypothesis is formulated: Spain and Argentina, having clearly differentiated features in economic structure, level of development, institutional frameworks and socio-historical processes, show common dynamics in the structuring of the capitalist labour market between a primary and secondary segment. Using equivalent databases on the workforce a typology of segmentation of employment is constructed that show, in addition to the specificities of each country, the similarities in the structuring of the labour market